Tetrahydropyrimidine-2-one compounds are known to be useful in pharmaceutical preparations. For example, U.S. Pat. No. 3,821,221 discloses a number of such compounds, and their effect as central nervous system stimulants or depressants. The compounds are said to be of value for therapeutic applications as potential psychotropic drugs.
As a result of pharmacological research into these tetrahydropyrimidine-2-one derivatives, it was discovered that icilin (also known as AG-3-5, chemical name 1-[2-hydroxyphenyl]-4-[2-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one) produced sensations of coldness when in contact with mucous membranes (nostrils, lips and eyelids) of the researchers, and also when ingested (see Wei et al, J. Pharm. Pharmacol. 1983, 35:110–112).
A known compound for producing a sensation of cold is menthol (2-isopropyl-5-methyl-cyclohexanol), which has been extensively applied as an additive in, for example, foodstuffs and oral hygiene products. It is used primarily because it elicits a sensation of coolness in the mouth, and because it has a pleasing mint flavour and odour. The cooling effect of menthol is due to the action of menthol on the nerve endings of the human body which detect hot and cold stimuli. In particular, menthol is believed to activate cold receptors on nerve endings. However, the use of menthol is limited by its strong minty smell and relative volatility.
It was found that icilin was capable of producing the same cooling effect as menthol. Icilin has a number of advantages over menthol, for example it is more potent, and has a lower acute toxicity, due to its lack of anaesthetic properties. Icilin was considered to be a particularly useful compound for pharmacological applications because it lacks the flavour and odour of menthol and is not readily absorbed through the skin. However, icilin has not been disclosed as a replacement for menthol for non-pharmaceutical applications.